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1.
Gene ; 764: 145094, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32860898

RESUMO

Long chain acyl-CoA synthetases (ACSLs), which drive the conversion of long chain fatty acid into acyl-CoA, an ingredient of lipid synthesis, have been well-acknowledged to exert an indispensable role in many metabolic processes in mammals, especially lipid metabolism. However, in chicken, the evolutionary characteristics, expression profiles and regulatory mechanisms of ACSL gene family are rarely understood. Here, we analyzed the genomic synteny, gene structure, evolutionary event and functional domains of the ACSL gene family members using bioinformatics methods. The spatiotemporal expression profiles of ACSL gene family, and their regulatory mechanism were investigated via bioinformatics analysis incorporated with in vivo and in vitro estrogen-treated experiments. Our results indicated that ACSL2 gene was indeed evolutionarily lost in the genome of chicken. Chicken ACSLs shared an AMP-binding functional domain, as well as highly conversed ATP/AMP and FACS signature motifs, and were clustered into two clades, ACSL1/5/6 and ACSL3/4, based on high sequence similarity, similar gene features and conversed motifs. Chicken ACSLs showed differential tissue expression distributions, wherein the significantly decreased expression level of ACSL1 and the significantly increased expression level of ACSL5 were found, respectively, the expression levels of the other ACSL members remained unchanged in the liver of peak-laying hens versus pre-laying hens. Moreover, the transcription activity of ACSL1, ACSL3 and ACSL4 was silenced and ACSL6 was activated by estrogen, but no response to ACSL5. In conclusion, though having highly conversed functional domains, chicken ACSL gene family is organized into two separate groups, ACSL1/5/6 and ACSL3/4, and exhibits varying expression profiles and estrogen effects. These results not only pave the way for better understanding the specific functions of ACSL genes in avian lipid metabolism, but also provide a valuable evidence for gene family characteristics.


Assuntos
Galinhas/genética , Coenzima A Ligases/genética , Evolução Molecular , Metabolismo dos Lipídeos/genética , Família Multigênica/genética , Acil Coenzima A/metabolismo , Animais , Células Cultivadas , Embrião de Galinha , Galinhas/crescimento & desenvolvimento , Galinhas/metabolismo , Coenzima A Ligases/metabolismo , Biologia Computacional , Estrogênios/metabolismo , Ácidos Graxos/metabolismo , Feminino , Perfilação da Expressão Gênica , Regulação da Expressão Gênica no Desenvolvimento , Hepatócitos , Cultura Primária de Células , Domínios Proteicos/genética , Análise Espaço-Temporal , Sintenia
2.
Sci Total Environ ; 751: 141766, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32889472

RESUMO

The occurrence of biologically potent sex hormones in agricultural soils is of growing concern due to their ability to disrupt the endocrine systems of aquatic organisms after being transported to surface waters via runoff. This study, therefore, examined the large-scale occurrence of 34 natural and synthetic sex hormones (13 progestins, 16 androgens, and 5 estrogens) in soils from 7 provinces and 1 municipality in China. The target sex hormones were detected in 99.3% of the soil samples, indicating their widespread occurrence in most agricultural areas. Additionally, seven synthetic progestins were detected in soils for the first time. The total concentration of the 34 sex hormones (Σsex hormones) in the sampled soils ranged from below the method detection limit to 23.7 ng/g (mean of 4.72 ± 4.07 ng/g), with androgens and progestins being the most dominant hormone groups. Significant correlations were observed among the concentrations of Σestrogens, Σandrogens, and Σprogestins (r = 0.117-0.433, p < 0.001), suggesting similar sources of sex hormones. The mean concentration of Σsex hormones varied considerably across the selected provinces/municipality. Notably, the annual slaughter of poultry and swine (R2 = 0.75-0.88), female population (R2 = 0.57-0.58), and soil organic carbon content (R2 = 0.20-0.55) in each province were significantly correlated with the concentrations or mean concentrations of Σsex hormones, Σestrogens, or Σprogestins. This finding implies that these parameters contributed to the occurrence and distribution of sex hormones in the studied soils. Finally, risk quotients for some sex hormones exceeded 0.01, indicating medium or high risks to agroecosystems. This study highlights the importance of designing an optimal manure fertilization strategy in order to mitigate the risks posed by sex hormones in agroecosystems.


Assuntos
Androgênios , Poluentes do Solo , Androgênios/análise , Animais , Carbono , China , Monitoramento Ambiental , Estrogênios/análise , Congêneres da Progesterona , Progestinas/análise , Solo , Poluentes do Solo/análise , Suínos
4.
J Environ Qual ; 49(5): 1322-1333, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-33016441

RESUMO

Antibiotics and estrogens are recognized as emerging contaminants in the water environment because of their potentially adverse effects on aquatic ecosystems. The concentrations of four steroid estrogens (17α-estradiol, 17ß-estradiol, estrone, and estriol) and eight antibiotics (norfloxacin, levofloxacin, ciprofloxacin, enrofloxacin, metronidazole, sulfapyridine, doxycycline, and sulfamethoxazole) in the Chaohu Lake basin in Anhui province, China, were analyzed along with adjacent wastewater. The levels of the target antibiotics and estrogens were below detection limits (not detected [nd])-89.86 and nd-118.09 ng L-1 , respectively, in the lake water. All of the target antibiotics and estrogens were detected in sediment, and the concentrations ranged widely (nd-35,544 and nd-16,344 ng kg-1 , respectively). Antibiotics and estrogens varied spatially in the study area and mostly came from untreated wastewater. Antibiotics and estrogens were associated with water parameters such as pH and total nitrogen. A significant positive correlation was observed between estriol and levofloxacin concentrations (r = .65; p < .01), indicating that levofloxacin from the same source might have inhibited the microbiological degradation of estriol in the surface water. Overall, the estrogens pose a more severe risk than antibiotics to the Chaohu Lake system. However, co-occurrence of antibiotics may affect the fate of estrogens in the same lake media. More attention should be given to estrogens than to antibiotics in wastewater-affected lake systems.


Assuntos
Águas Residuárias , Poluentes Químicos da Água/análise , Antibacterianos/análise , China , Ecossistema , Monitoramento Ambiental , Estrogênios/análise , Lagos/análise
5.
Eur J Endocrinol ; 183(6): 561-569, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-33055297

RESUMO

Objective: The impact of different combinations of long-term gender-affirming hormone therapy (GAHT) in transwomen (TW) is largely unknown. To assess the effects of 5-year administration of cyproterone acetate (CPA) or leuprolide acetate (Leu) plus transdermal or oral estradiol (E). Design: Cohort study based on prospectively collected data. Fifty TW received 50 mg CPA daily orally (n = 25; CPA+E group) or 3.75 mg Leu i.m. monthly (n = 25; Leu+E group) with 1 or 2 mg E daily for 5 years. Reproductive hormones, biochemical and anthropometric parameters, body composition and bone mineral density (BMD) were assessed. Results: LH, FSH and total testosterone levels were similarly and significantly suppressed in both groups. Prolactin increased only in the CPA+E group (P = 0.002). Fasting insulin resistance and glucose progressively increased in the CPA+E group only (treatment × time effect P = 0.002 and P = 0.043, respectively). Total cholesterol increased more in the Leu+E group than in the CPA+E group and HDL-cholesterol decreased in the CPA+E group (time × treatment interaction effect, P = 0.007). Lumbar and total body BMD increased in both groups after 3 years. No serious adverse events were recorded. Conclusions: Both regimens were effective in suppression of T production. CPA+E worsened the metabolic profile with a slight increase in PRL levels. All subjects presented an increase in BMD regardless of treatment. These preliminary data could have clinical implications in the choice of GAHT, in particular for those TW not requiring gender-affirming surgery.


Assuntos
Acetato de Ciproterona/administração & dosagem , Estradiol/administração & dosagem , Leuprolida/administração & dosagem , Testosterona/sangue , Transexualidade/sangue , Transexualidade/tratamento farmacológico , Adulto , Antagonistas de Androgênios/administração & dosagem , Estudos de Coortes , Esquema de Medicação , Quimioterapia Combinada , Estrogênios/administração & dosagem , Feminino , Fármacos para a Fertilidade Feminina/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Testosterona/antagonistas & inibidores , Pessoas Transgênero
6.
Anticancer Res ; 40(11): 5995-6002, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33109537

RESUMO

Steroid contraceptive hormones may promote human papilloma virus (HPV) - DNA integration into the host genome, may bind to specific HPV-DNA sequences within transcriptional regulatory regions, and may modulate cell apoptosis. Most epidemiological studies, reported in this narrative review, have shown that oral contraception is associated with a 1.5-3.3-fold higher relative risk of cervical carcer, but only in users for >5 years and especially in HPV-positive women. The relative risk declines with increasing time since last use and is not different from that of never users after >10 years. Ten-year oral contraceptive use from the age of 20 years is associated with an increase in the cumulative incidence of invasive cervical cancer at the age of 50 years of approximately 1 case per 1,000. Oral contraception has a very small negative impact on the absolute risk of cancer of the uterine cervix.


Assuntos
Anticoncepcionais/efeitos adversos , Estrogênios/efeitos adversos , Progestinas/efeitos adversos , Neoplasias do Colo do Útero/epidemiologia , Neoplasias do Colo do Útero/etiologia , Feminino , Humanos , Papillomaviridae/fisiologia , Fatores de Risco , Neoplasias do Colo do Útero/virologia
7.
Eur J Endocrinol ; 183(5): 529-536, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33071222

RESUMO

Objective: Transgender individuals sometimes report a lack of physical change during hormone treatment, such as alterations in muscle tone or fat distribution. Identifying characteristics of this subgroup could be a step toward individualizing hormone therapy in transgender individuals. Therefore, we study the variation of changes in body composition and characteristics associated with a lack of change. Design and methods: Body composition measures were recorded in 323 transmen and 288 transwomen at every visit from the start of hormone therapy to a maximum of 24 months follow-up. Absence of change was defined as transmen with a decrease in lean body mass or transwomen with a decrease in fat percentage. Results: A lack of change at 24 months was observed in 19 of 94 (20.2%) transmen and in 9 of 96 (9.4%) transwomen. The risk of not achieving change in body composition was related to lower testosterone levels and less suppression of LH in transmen (OR: 0.67, 95% CI: 0.48-0.94 per SD increase in testosterone and OR: 1.36, 95% CI: 1.01-1.83 per SD increase in LH). Conclusions: There is a large variation in body composition changes during hormone therapy, with a substantial proportion of individuals with no measurable effects. In transmen, serum testosterone and LH were associated with a lack of change, but serum hormone levels were not associated with body composition changes in transwomen. The results provide a rationale for individualizing hormone therapy in transmen, by considering individual effects rather than solely relying on a standardized dosage of hormone therapy.


Assuntos
Antagonistas de Androgênios/uso terapêutico , Androgênios/uso terapêutico , Composição Corporal , Estradiol/uso terapêutico , Estrogênios/uso terapêutico , Testosterona/uso terapêutico , Pessoas Transgênero , Adulto , Distribuição da Gordura Corporal , Acetato de Ciproterona/uso terapêutico , Relação Dose-Resposta a Droga , Impedância Elétrica , Estradiol/sangue , Feminino , Humanos , Hormônio Luteinizante/sangue , Masculino , Medicina de Precisão , Procedimentos de Readequação Sexual/métodos , Testosterona/análogos & derivados , Testosterona/sangue , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
8.
Nat Commun ; 11(1): 5488, 2020 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-33127913

RESUMO

The 17q23 amplicon is associated with poor outcome in ER+ breast cancers, but the causal genes to endocrine resistance in this amplicon are unclear. Here, we interrogate transcriptome data from primary breast tumors and find that among genes in 17q23, PRR11 is a key gene associated with a poor response to therapeutic estrogen suppression. PRR11 promotes estrogen-independent proliferation and confers endocrine resistance in ER+ breast cancers. Mechanistically, the proline-rich motif-mediated interaction of PRR11 with the p85α regulatory subunit of PI3K suppresses p85 homodimerization, thus enhancing insulin-stimulated binding of p110-p85α heterodimers to IRS1 and activation of PI3K. PRR11-amplified breast cancer cells rely on PIK3CA and are highly sensitive to PI3K inhibitors, suggesting that PRR11 amplification confers PI3K dependence. Finally, genetic and pharmacological inhibition of PI3K suppresses PRR11-mediated, estrogen-independent growth. These data suggest ER+/PRR11-amplified breast cancers as a novel subgroup of tumors that may benefit from treatment with PI3K inhibitors and antiestrogens.


Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Moduladores de Receptor Estrogênico/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas/genética , Proteínas/metabolismo , Transdução de Sinais/efeitos dos fármacos , Animais , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Modelos Animais de Doenças , Resistencia a Medicamentos Antineoplásicos , Antagonistas de Estrogênios/farmacologia , Moduladores de Receptor Estrogênico/uso terapêutico , Estrogênios , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Insulina , Camundongos Nus , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Zhongguo Zhong Yao Za Zhi ; 45(16): 3770-3775, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32893569

RESUMO

The coordination and unification of Yin and Yang are the basis of normal human life activities. Along with the age growth and aging of the body, women will suffer from menopausal syndrome during menopause. In addition to the significant changes in the genital system, there are also pathological manifestations in estrogen target points including bone, nerve and cardiovascular systems, due to the imbalance of Yin and Yang. Besides the insufficiency of estrogen, the main cause of menopausal syndrome is the changes in the response of target organs to estrogen. In other words, the biological effects mediated by estrogen receptor(ER) alpha and beta subtypes in target cells are often different or even opposite; the changes of expression level and ratio of ERα and ERß are also important causes for the abnormal estrogenic effects in target organs and the imbalance of Yin and Yang of the body. Therefore, on one hand, the therapeutic mechanism of drugs is ER-mediated estrogenic effect. On the other hand, the drugs have a regulatory effect on ER subtype expression in target cells and Yin-Yang state in target organs and even organisms, so as to cause further changes in the response of target cells to estrogen or estrogenic components, and exert its therapeutic effects. This paper reviews the pharmacological mechanism of gynecological traditional Chinese medicine in harmonizing Yin and Yang in estrogen-positive target cells and the clinical efficacy in the following aspects, including estrogen and its mechanism, the estrogenic effect of ER in traditional Chinese medicine and the mechanism of ER subtype in balancing Yin and Yang and mediating and regulating the main target tissues in menopausal syndrome treatment.


Assuntos
Receptor beta de Estrogênio , Yin-Yang , Receptor alfa de Estrogênio , Estrogênios , Feminino , Humanos , Medicina Tradicional Chinesa
10.
Medicine (Baltimore) ; 99(37): e22163, 2020 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-32925779

RESUMO

For frozen embryo transplantation patients who failed to use hormone replacement cycle (HRC) transplantation for 2 consecutive times, the third time of transplantation was divided into 2 groups: HRC and natural cycle (NC), and the pregnancy rate of the 2 groups, especially the clinical pregnancy rate, was compared.Retrospective study of 174 patients in the reproductive medicine center of an affiliated hospital of Shandong University of Traditional Chinese Medicine between January 2015 and September 2018.The 174 patients were all infertile with regular menstruation. They had undergone 2 consecutive failed cycles of endometrial preparation with hormone replacement therapy and prepare for the third frozen embryo transplantation.A third cycle of treatment was planned using either NC or HRC for endometrial preparation. All the embryos were obtained during the same oocyte retrieval cycle. Patients were divided into groups based on the method of endometrial preparation: 98 were classified as NC and 76 as HRC.The pregnancy outcomes for the 2 groups were compared. Confounding factors that may affect clinical pregnancy rates were analyzed.We found that on the day of endometrial transformation, estrogen levels and endometrial thickness in the NC group were significantly higher than those in the HRC group. There were no significant differences in the rates of biochemical pregnancy, clinical pregnancy, cumulative pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy, or live birth between the 2 groups. It is concluded by binary regression analysis that the different endometrial preparation protocol have no significant effect on the CPR.NC is as effective as HRC after 2 previous cycles of HRC. Because this was a retrospective study design, selection bias is possible, although the baseline characteristics of the 2 groups of patients were matched.


Assuntos
Transferência Embrionária/métodos , Terapia de Reposição Hormonal/métodos , Resultado da Gravidez/epidemiologia , Taxa de Gravidez , Adulto , Implantação do Embrião/fisiologia , Endométrio/metabolismo , Estrogênios/sangue , Feminino , Humanos , Gravidez , Estudos Retrospectivos
11.
Nat Commun ; 11(1): 4642, 2020 09 15.
Artigo em Inglês | MEDLINE | ID: mdl-32934200

RESUMO

Epigenetic regulation plays an important role in governing stem cell fate and tumorigenesis. Lost expression of a key DNA demethylation enzyme TET2 is associated with human cancers and has been linked to stem cell traits in vitro; however, whether and how TET2 regulates mammary stem cell fate and mammary tumorigenesis in vivo remains to be determined. Here, using our recently established mammary specific Tet2 deletion mouse model, the data reveals that TET2 plays a pivotal role in mammary gland development and luminal lineage commitment. We show that TET2 and FOXP1 form a chromatin complex that mediates demethylation of ESR1, GATA3, and FOXA1, three key genes that are known to coordinately orchestrate mammary luminal lineage specification and endocrine response, and also are often silenced by DNA methylation in aggressive breast cancers. Furthermore, Tet2 deletion-PyMT breast cancer mouse model exhibits enhanced mammary tumor development with deficient ERα expression that confers tamoxifen resistance in vivo. As a result, this study elucidates a role for TET2 in governing luminal cell differentiation and endocrine response that underlies breast cancer resistance to anti-estrogen treatments.


Assuntos
Diferenciação Celular , Proteínas de Ligação a DNA/metabolismo , Estradiol/metabolismo , Estrogênios/metabolismo , Glândulas Mamárias Animais/metabolismo , Proteínas Proto-Oncogênicas/metabolismo , Animais , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/fisiopatologia , Linhagem da Célula , Metilação de DNA , Proteínas de Ligação a DNA/genética , Sistema Endócrino/metabolismo , Epigênese Genética , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Glândulas Mamárias Animais/fisiopatologia , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética
12.
Aquat Toxicol ; 227: 105586, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32882451

RESUMO

Estrogenic effects triggered by androgens have been previously shown in a few studies. Aromatization and direct binding to estrogen receptors (ERs) are the most proposed mechanisms. For example, previously, a modulation of vitellogenin A (VtgA) by testosterone (T), an aromatizable androgen, was reported in brown trout primary hepatocytes. The effect was reversed by an ER antagonist. In this study, using the same model the disruption caused by T and by the non-aromatizable androgen - dihydrotestosterone (DHT), was assessed in selected estrogenic targets. Hepatocytes were exposed (96 h) to six concentrations of each androgen. The estrogenic targets were VtgA, ERα, ERß1 and two zona pellucida genes, ZP2.5 and ZP3a.2. The aromatase CYP19a1 gene and the androgen receptor (AR) were also included. Modulation of estrogenic targets was studied by quantitative real-time PCR and immunohistochemistry, using an HScore system. VtgA and ERα were up-regulated by DHT (1, 10, 100 µM) and T (10, 100 µM). In contrast, ERß1 was down-regulated by DHT (10, 100 µM), and T (100 µM). ZP2.5 mRNA levels were increased by DHT and T (1, 10, 100 µM), while ZP3a.2 was up-regulated by DHT (100 µM) and T (10, 100 µM). Positive correlations were found between VtgA and ERα mRNA levels and ZPs and ERα, after exposure to both androgens. The mRNA levels of CYP19a1 were not changed, while AR expression tended to increase after micromolar DHT exposures. HScores for Vtg and ZPs corroborated the molecular findings. Both androgens triggered estrogen signaling through direct binding to ERs, most probably ERα.


Assuntos
Androgênios/toxicidade , Di-Hidrotestosterona/toxicidade , Estrogênios/metabolismo , Hepatócitos/efeitos dos fármacos , Testosterona/toxicidade , Truta/metabolismo , Poluentes Químicos da Água/toxicidade , Androgênios/metabolismo , Animais , Células Cultivadas , Di-Hidrotestosterona/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Estrogênios/genética , Expressão Gênica/efeitos dos fármacos , Hepatócitos/metabolismo , Masculino , Cultura Primária de Células , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Testosterona/metabolismo , Vitelogeninas/genética , Vitelogeninas/metabolismo , Poluentes Químicos da Água/metabolismo
13.
Anticancer Res ; 40(10): 5649-5657, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32988889

RESUMO

BACKGROUND: In recent years, GATA-binding protein 3 (GATA3) has been indicated as a marker showing good prognosis in breast cancer. In luminal breast cancer, which has good a prognosis, it shows more significant elevation in small-sized and low-grade tumors. In contrast, Ki-67 is defined as a poor prognostic factor. The aim of this study was to emphasise the prognostic importance of GATA3 and the inverse relationship with Ki-67. MATERIALS AND METHODS: In our study, 90 patients with invasive ductal breast cancer were immunohistochemically evaluated for Ki-67 and GATA3 expression. The relationship between GATA3 and Ki-67 expression was examined. In addition, the relationship between these two factors with estrogen, progesterone, human epidermal growth factor 2 receptor antibodies and other prognostic parameters such as disease-free survival and local recurrence was investigated. We accepted the level of ≥5% nüclear reaction as positive for GATA 3. A Ki-67 cut-off value of 20% was accepted as positive. RESULTS: In GATA3 positive breast cancers, good prognostic parameters were seen including high estrogen receptor (ER) positivity, progesterone receptor (PR) positivity, small tumor size and low histological grade as well as low Ki-67 expression. In breast cancers showing high Ki-67 expression, ER, PR, and GATA3 positivity were lower and there was higher human epidermal growth factor receptor 2 (HER2) positivity and high histological grade while the tumor size was larger. CONCLUSION: Our study has revealed that GATA3 has an inverse relationship with Ki-67, whereas it has a positive releationship with good prognostic factors.


Assuntos
Carcinoma Ductal de Mama/genética , Fator de Transcrição GATA3/genética , Antígeno Ki-67/genética , Recidiva Local de Neoplasia/genética , Adulto , Biomarcadores Tumorais , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/patologia , Intervalo Livre de Doença , Estrogênios/genética , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Progesterona/genética , Prognóstico , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Receptores de Progesterona/genética
14.
Chemosphere ; 258: 127361, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32947662

RESUMO

In female mammals, puberty and fertility are regulated by the synthesis of estradiol (E2) by the ovaries at the infantile stage and at the approach of puberty, a process which may be affected by endocrine disrupting chemicals (EDC)s acting through the Aryl hydrocarbon receptor (AhR). However, there is no information on AhR-mediated regulation of ovarian estrogenic activity during these developmental periods. Here, we assessed in mouse models, the intrinsic and exogenous ligand-induced AhR action on E2 synthesis at the infantile stage (14 days postnatal (dpn)) and at the approach of puberty (28 dpn). Intrinsic AhR pathway became activated in the ovary at the approach of puberty, as suggested by the decreased intra-ovarian expression in prototypical and steroidogenesis-related AhR targets and E2 contents in Ahr knockout (Ahr-/-) mice versus Ahr+/+ mice exclusively at 28 dpn. Accordingly, AhR nuclear localization in granulosa cells, reflecting its activity in cells responsible for E2 synthesis, was much lower at 14 dpn than at 28 dpn in C57BL/6 mice. However, AhR signaling could be activated by exogenous ligands at both ages, as revealed by FICZ- and TCDD-induced Ahrr and Cyp1a1 expression in C57BL/6 mice. Nevertheless, TCDD impacted ovarian estrogenic activity only at 28 dpn. This age-related AhR action may be ligand-dependent, since FICZ had no effect on E2 synthesis at 28 dpn. In conclusion, AhR would not regulate ovarian estrogenic activity before the approach of puberty. Its activation by EDCs may be more detrimental to reproductive health at this stage than during infancy.


Assuntos
Ovário/fisiologia , Dibenzodioxinas Policloradas/toxicidade , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Citocromo P-450 CYP1A1/metabolismo , Disruptores Endócrinos/metabolismo , Estradiol/metabolismo , Estrogênios/farmacologia , Feminino , Células da Granulosa/efeitos dos fármacos , Ligantes , Camundongos , Camundongos Endogâmicos C57BL , Ovário/efeitos dos fármacos , Dibenzodioxinas Policloradas/metabolismo , Maturidade Sexual/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos
16.
BMJ Open ; 10(9): e040644, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32928868

RESUMO

OBJECTIVE: To review evidence on routinely prescribed drugs in the UK that could upregulate or downregulate ACE2 and potentially affect COVID-19 disease. DESIGN: Systematic review. DATA SOURCE: MEDLINE, EMBASE, CINAHL, the Cochrane Library and Web of Science. STUDY SELECTION: Any design with animal or human models examining a currently prescribed UK drug compared with a control, placebo or sham group, and reporting an effect on ACE2 level, activity or gene expression. DATA EXTRACTION AND SYNTHESIS: MEDLINE, EMBASE, CINAHL, the Cochrane Library, Web of Science and OpenGrey from inception to 1 April 2020. Methodological quality was assessed using the SYstematic Review Centre for Laboratory animal Experimentation (SYRCLE) risk-of-bias tool for animal studies and Cochrane risk-of-bias tool for human studies. RESULTS: We screened 3360 titles and included 112 studies with 21 different drug classes identified as influencing ACE2 activity. Ten studies were in humans and one hundred and two were in animal models None examined ACE2 in human lungs. The most frequently examined drugs were angiotensin receptor blockers (ARBs) (n=55) and ACE inhibitors (ACE-I) (n=22). More studies reported upregulation than downregulation with ACE-I (n=22), ARBs (n=55), insulin (n=8), thiazolidinedione (n=7) aldosterone agonists (n=3), statins (n=5), oestrogens (n=5) calcium channel blockers (n=3) glucagon-like peptide 1 (GLP-1) agonists (n=2) and Non-steroidal anti-inflammatory drugs (NSAIDs) (n=2). CONCLUSIONS: There is an abundance of the academic literature and media reports on the potential of drugs that could attenuate or exacerbate COVID-19 disease. This is leading to trials of repurposed drugs and uncertainty among patients and clinicians concerning continuation or cessation of prescribed medications. Our review indicates that the impact of currently prescribed drugs on ACE2 has been poorly studied in vivo, particularly in human lungs where the SARS-CoV-2 virus appears to enact its pathogenic effects. We found no convincing evidence to justify starting or stopping currently prescribed drugs to influence outcomes of COVID-19 disease.


Assuntos
Antagonistas de Receptores de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Bloqueadores dos Canais de Cálcio/farmacologia , Infecções por Coronavirus , Estrogênios/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Hipoglicemiantes/farmacologia , Pandemias , Peptidil Dipeptidase A/efeitos dos fármacos , Pneumonia Viral , Anti-Inflamatórios não Esteroides/farmacologia , Betacoronavirus/metabolismo , Regulação para Baixo , Peptídeo 1 Semelhante ao Glucagon/agonistas , Humanos , Insulina/farmacologia , Antagonistas de Receptores de Mineralocorticoides/farmacologia , Peptidil Dipeptidase A/metabolismo , Tiazolidinedionas/farmacologia , Reino Unido , Regulação para Cima
17.
Sci Total Environ ; 740: 140050, 2020 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-32927569

RESUMO

Biological assays can evaluate the cumulative effect of a mixture, considering synergistic/antagonistic interactions and effects of unknown/unconsidered compounds. Therefore, their application could increase in the next years also to analyse biological samples. The aim of this review is to discuss the methodological approach and the application of estrogenic activity assays in human biological samples. 75 research articles were analysed and divided according to whether they used these assays: i) to quantify the level of estrogens and/or as a biomarker of estrogenic status ii) as a biomarker of exposure to endocrine disrupting chemicals (EDCs). For the first purpose, some authors extracted biological samples while others tested them directly without any treatment. The study of these methodologies outlined that the methodology applied influenced the specificity of analysis. The estrogenic activity biomarker was used to analyse physiological variations of estrogens, pediatric diseases, hormone-dependent diseases and estrogen suppression/enhancement after pharmaceutical treatments. For the second purpose, some authors extracted samples while others tested them directly, some authors divided endogenous estrogens from xenoestrogens while others tested samples without separation. The analysis of these methodologies outlined some limitations related to the efficiency of extraction and the incorrect separation of some compounds. The studies which applied this EDC biomarker showed that it was correlated with some EDCs, it varied according to the exposure of the population and it allowed the identification of some relationships between EDC exposure and breast cancer, type 1 diabetes and adverse health effects on children. In conclusion, the estrogenic activity of biological samples can be a useful tool: to quantify low levels of 17ß-estradiol, to assess the combined effect of endogenous estrogens and xenoestrogens, to estimate the estrogenic status providing considerable insight into physiological or pathological conditions, to evaluate EDC presence implementing the existing knowledge about EDC exposure and adverse health effects.


Assuntos
Disruptores Endócrinos , Biomarcadores , Criança , Estradiol , Estrogênios , Estrona , Humanos
18.
Monaldi Arch Chest Dis ; 90(4)2020 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-32945643

RESUMO

Novel coronavirus disease (COVID-19) has affected nearly 7 million individuals and claimed more than 0.4 million lives to date. There are several reports of gender differences related to infection and death due to COVID-19. This raises important questions such as "Whether there are differences based on gender in risk and severity of infection or mortality rate?" and "What are the biological explanation and mechanisms underlying these differences?" Emerging evidences have proposed sex-based immunological, genetic, and hormonal differences to explain this ambiguity. Besides biological differences, women have also faced social inequities and economic hardships due to this pandemic. Several recent studies have shown that independent of age males are at higher risk for severity and mortality in COVID-19 patients. Although susceptibility to SARS-CoV-2 was found to be similar across both genders in several disease cohorts, a disproportionate death ratio in men can be partly explained by the higher burden of pre-existing diseases and occupational exposures among men. At immunological point of view, females can engage a more active immune response, which may protect them and counter infectious diseases as compared to men. This attribute of better immune responses towards pathogens is thought to be due to high estrogen levels in females. Here we review the current knowledge about sex differences in susceptibility, the severity of infection and mortality, host immune responses, and the role of sex hormones in COVID-19 disease.


Assuntos
Imunidade Adaptativa/imunologia , Infecções por Coronavirus/imunologia , Estrogênios/imunologia , Imunidade Inata/imunologia , Pneumonia Viral/imunologia , Testosterona/imunologia , Betacoronavirus , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/mortalidade , Suscetibilidade a Doenças , Feminino , Humanos , Masculino , Mortalidade , Pandemias , Pneumonia Viral/epidemiologia , Pneumonia Viral/mortalidade , Índice de Gravidade de Doença , Caracteres Sexuais , Fatores Sexuais
20.
PLoS Comput Biol ; 16(9): e1008191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32970665

RESUMO

Environmental toxicants affect human health in various ways. Of the thousands of chemicals present in the environment, those with adverse effects on the endocrine system are referred to as endocrine-disrupting chemicals (EDCs). Here, we focused on a subclass of EDCs that impacts the estrogen receptor (ER), a pivotal transcriptional regulator in health and disease. Estrogenic activity of compounds can be measured by many in vitro or cell-based high throughput assays that record various endpoints from large pools of cells, and increasingly at the single-cell level. To simultaneously capture multiple mechanistic ER endpoints in individual cells that are affected by EDCs, we previously developed a sensitive high throughput/high content imaging assay that is based upon a stable cell line harboring a visible multicopy ER responsive transcription unit and expressing a green fluorescent protein (GFP) fusion of ER. High content analysis generates voluminous multiplex data comprised of minable features that describe numerous mechanistic endpoints. In this study, we present a machine learning pipeline for rapid, accurate, and sensitive assessment of the endocrine-disrupting potential of benchmark chemicals based on data generated from high content analysis. The multidimensional imaging data was used to train a classification model to ultimately predict the impact of unknown compounds on the ER, either as agonists or antagonists. To this end, both linear logistic regression and nonlinear Random Forest classifiers were benchmarked and evaluated for predicting the estrogenic activity of unknown compounds. Furthermore, through feature selection, data visualization, and model discrimination, the most informative features were identified for the classification of ER agonists/antagonists. The results of this data-driven study showed that highly accurate and generalized classification models with a minimum number of features can be constructed without loss of generality, where these machine learning models serve as a means for rapid mechanistic/phenotypic evaluation of the estrogenic potential of many chemicals.


Assuntos
Algoritmos , Estrogênios/classificação , Aprendizado de Máquina , Linhagem Celular , Estrogênios/metabolismo , Humanos , Receptores Estrogênicos/metabolismo
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